Protective effects of melatonin against oxidative stress in Fmr1 knockout mice: a therapeutic research model for the fragile X syndrome.

Abstract

Fragile X syndrome is the most common form of inherited mental retardation. It is typically caused by a mutation of the Fragile X mental-retardation 1 (Fmr1) gene. To better understand the role of the Fmr1 gene and its gene product, the fragile X mental-retardation protein in central nervous system functions, an fmr1 knockout mouse that is deficient in the fragile X mental-retardation protein was bred. In the present study, fragile X mental retardation 1-knockout and wild-type mice are used to determine behaviour and oxidative stress alterations, including reduced glutathione, oxidized glutathione and thiobarbituric acid-reactive substances, before and after chronic treatment with melatonin or tianeptine. Reduced glutathione levels were reduced in the brain of fmr1-knockout mice and chronic melatonin treatment normalized the glutathione levels compared with the control group. Lipid peroxidation was elevated in brain and testes of fmr1-knockout mice and chronic melatonin treatment prevents lipid peroxidation in both tissues. Interestingly, chronic treatment with melatonin alleviated the altered parameters in the fmr1-knockout mice, including abnormal context-dependent exploratory and anxiety behaviours and learning abnormalities. Chronic treatment with tianeptine (a serotonin reuptake enhancer) did not normalize the behaviour in fmr1-knockout mice. The prevention of oxidative stress in the fragile X mouse model, by an antioxidant compound such as melatonin, emerges as a new and promising approach for further investigation on treatment trials for the disease.

• Authors: Yanina Romero-Zerbo, Juan Decara, Rajaa el Bekay, Lourdes Sanchez-Salido, Ignacio Del Arco-Herrera, Fernando Rodríguez de Fonseca, Yolanda de Diego-Otero
• Journal: Journal of pineal research (J Pineal Res) Vol. 46 Issue 2 Pg. 224-34 (Mar 2009) ISSN: 1600-079X [Electronic] England
• PMID: 19141086 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antioxidants
• Fmr1 protein, mouse
• Thiobarbituric Acid Reactive Substances
• Fragile X Mental Retardation Protein
• Glutathione
• Melatonin

Topics

• Animals
• Antioxidants (pharmacology, therapeutic use)
• Behavior, Animal (drug effects)
• Disease Models, Animal
• Fragile X Mental Retardation Protein (genetics)
• Fragile X Syndrome (drug therapy, genetics, metabolism)
• Glutathione (metabolism)
• Humans
• Lipid Peroxidation (drug effects)
• Melatonin (pharmacology, therapeutic use)
• Mice
• Mice, Knockout
• Oxidative Stress (drug effects)
• Thiobarbituric Acid Reactive Substances (metabolism)